The protein kinase C family is a group of serine/threonine kinases that is comprised of twelve related isoenzymes. These kinases are expressed in a wide range of tissues and cell types. The PKC-theta isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, and the subsequent release of cytokines such as IL-2 and T cell proliferation (Isakov and Altman, Annu. Rev. Immunol., 2002, 20, 761-94).
It has been well established that T cells play an important role in regulating the immune response (Powrie and Coffman, Immunology Today, 1993, 14, 270). The activation of T cells is often the initiating event in a variety of immunological disorders. It is believed that following activation of the TCR, there is an influx of calcium that is required for T cell activation. Upon activation, T cells produce cytokines, including IL-2, leading to cell proliferation, differentiation, and effector function. Clinical studies with inhibitors of IL-2 have shown that interference with T cell activation and proliferation effectively suppresses immune response in vivo (Waldmann, Immunology Today, 1993, 14, 264). Accordingly, agents that inhibit T lymphocyte activation and subsequent cytokine production are therapeutically useful for selectively suppressing the immune response in a patient in need of such immunosuppression and therefore are useful in treating immunological disorders such as autoimmune and inflammatory diseases.
Additionally, PKC-theta activation has been shown to play a role in insulin resistance in skeletal muscle and therefore inhibitors of PKC-theta may also be useful for treating type II diabetes (M. E. Griffen et al., Diabetes, 1999, 48, 1270). PKC-theta activation has also been implicated in leukemia and thus inhibitors of PKC-theta may be useful for the treatment of leukemia (Villalba and Altman, Current Cancer Targets, 2002, 2, 125).
There remains a need to develop effective therapeutic agents for the majority of the diseases and disorders associated with activation of PKC-theta. Accordingly, it would be beneficial to provide safe and effective compounds that are useful as inhibitors of PKC-theta and thus in the treatment of disorders and diseases associated with activation of PKC-theta.